Lung cancer is a clinically common malignant tumor in lungs. It is generally divided into two categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). The incidence of the non-small cell lung cancer all over the world is increasing year by year, which seriously threatens human health. Non-small cell lung cancer is the leading cause of cancer death in the United States, Japan, and Western European countries. For advanced patients, chemotherapy may improve survival to a certain extent, but chemotherapeutic drugs have significant toxicity to human body. Hence, there is a great need for therapeutic agents that can specifically target key genes involved in tumor growth (Schiller J H et al., N. Engl. J. Med., 346: 92-98, 2002).
ALK is an anaplastic lymphoma kinase (ALK). It was discovered in 2007 that there are rearrangements of echinoderm microtubule-associated protein-like 4 (EML4) gene and ALK gene due to chromosomal inversion in patients with lung cancer. Lung cancer with EML4-ALK gene rearrangement (also known as ALK-positive) is a newly discovered subtype that mainly occurs in NSCLC, accounting for approximately 3%-5% of lung cancer. The fusion protein encoded by the rearranged EML4-ALK fusion gene forms non-ligand dependent dimers, resulting in activation of constitutive ALK. ALK signal can lead to cell proliferation and production by activating RAS-MEK-ERK, JAK3-STAT3, and PI3K-AKT signaling pathways, thereby contributing to oncogenesis and progression of lung cancer. ALK translocation in NSCLC is associated with adenocarcinoma histology, signet ring cell morphology, young patients, and non-smoking history. A large-scale phase I study for Xalkori (crizotinib) which is an ALK inhibitor demonstrated an overall response rate of 57% and a disease control rate of 90% in cancer patients with ALK translocation, which resulted in FDA approval. More effective ALK inhibitors and strategies for targeting acquired drug resistance are under development. Although the proportion of ALK-positive NSCLC in lung cancer is very low, the number of new cases per year in China is still close to 35,000. Therefore, there is a need to accurately identify ALK-positive NSCLC, and offer an appropriate treatment.
EGFR (Epidermal Growth Factor Receptor) is a transmembrane glycoprotein which has tyrosine kinase activity and is widely distributed on cell membranes of various tissues of human body. Activating EGFR mutations are located in the tyrosine kinase domain and may cause constitutive EGFR signal. PI3K-AKT and RAS-MEK-ERK signals activated by EGFR mutation play a crucial role in growth, survival and migration of cancer cells. The most common activating mutations are an in-frame deletion mutation of exon 19 and a missense mutation of codon 858 (causing arginine to be replaced by leucine, L858R). Lung cancers with EGFR mutations are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). Currently, genotypic screening for EGFR mutations is often used to screen for patients who suffer from stage IV NSCLC and the first-line treatment for whom is to receive EGFR TKIs. The studies currently focus on prolonging the duration of the response and finding effective ways to target drug resistance mechanisms that are developed during disease progression. The most common drug resistance mechanism is EGFR/T790M mutation, which occurs in approximately 50% of resistant tumors. Certain other mechanisms such as MET amplification, PIK3CA mutation and transformation to SCLC have also been described.
By developing drugs that target cancer-specific gene mutations, the diagnosis and treatment of non-small cell lung cancer (NSCLC) have undergone major changes in recent years. Routine genetic testing of somatic mutations in lung cancer bioptic tissues is becoming the standard for providing the best medical care for the patients. Identification of specific mutations such as EGFR and ALK mutations provides guidance for the use of targeted therapies approved by FDA, which may be beneficial clinically. Discovery of other genetic mutations can also guide patients and physicians towards clinical trials of new targeted drugs.
Currently, tyrosine kinase inhibitors (TKI) that target EGFR (e.g., Iressa (Gefitinib) and Tarceva (Erlotinib)) have achieved great success in clinical treatment of non-small cell lung cancer. However, patients treated with TKI inhibitors often suffer from relapse due to the development of TKI resistance. Second-generation EGFR irreversible inhibitors such as Canertinib, Afatinib, Neratinib, Pelitinib etc. have entered clinical trials, but these molecules have poor selectivity for EGFR mutants, resulting in a low clinically tolerated drug dose. As a result, even when administrated at the maximum tolerated dose, the drug cannot reach the effective concentration in the body and thus is ineffective for most drug resistant patients.
In addition, according to the studies, in the treatment of non-small cell lung cancer sensitive to EGFR-TKI with Gefitinib or Erlotinib, patients often develop secondary drug resistance after 6-12 months, and about 50% among them have T790M mutation encoded by exon 20. Studies suggest that T790M mutation blocks the binding of EGFR with small-molecule inhibitors of EGFR (e.g., Gefitinib and Erlotinib) or increases the affinity of EGFR to ATP, resulting in drug resistance (Yun C H et al., Proc Natl Acad Sci USA. 2008 Feb. 12; 105(6):2070-5).
U.S. pharmaceutical giant Pfizer recently announced that the European Commission (EC) has approved product label updates for the extended use of oral targeted anti-cancer drug Crizotinib for the first-line treatment of adult patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer. Crizotinib is a small-molecule tyrosine kinase inhibitor (TKI) that targets anaplastic lymphoma kinase (ALK), ROS1 and MET, and was approved by FDA in 2011 for the treatment of patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC). Crizotinib is the world's first ALK inhibitor marketed and is currently approved in more than 80 countries. Clinically, Crizotinib is recognized as the standard nursing therapy for advanced ALK-positive NSCLC. Marketing of this drug has significantly changed the clinical care of patients with advanced ALK-positive NSCLC. To date, more than 20,000 patients have received Crizotinib therapy globally.
The compounds described herein are dual inhibitors of mutant EGFR and ALK that can be used alone or in combination with other therapeutic agents for the treatment of non-small cell lung cancer. Currently, there are reports of using the compounds described herein for the treatment of drug-resistant non-small cell lung cancer carrying EGFR T790M mutation and/or EGFR L858R mutation and/or EGFR delE746_A750 mutation and for first-line treatment of advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer.